RAS Quantification in Patients With Aliskiren or Candesartan (RASQAL)

Renin-Angiotensin-System Quantification in Patients Treated With Aliskiren or Candesartan (RASQAL)

Forced blockade of the renin-angiotensin-system (RAS) by using direct renin inhibition (DRI) has long been propagated to effectuate beneficial outcomes. However, recent large clinical trials have outlined harmful effects for DRI in combination with other forms of RAS blockade. To date, information regarding DRI as RAS-blocking monotherapy is very limited. Furthermore, it remains to be elucidated how DRI and angiotensin receptor blockers affect the so-called 'classical' and 'alternative' RAS molecularly. As components of the 'alternative' RAS (e.g. Ang 1-7) have moved into research focus, it would be of importance to determine angiotensin regulation with medical RAS blockade.

In this prospective, single-center randomized trial over 10 weeks, 24 patients with chronic kidney disease (CKD) stage III-IV (eGFR 15-59 ml/min) will be randomized to take either aliskiren (up to 300 mg per day) or candesartan (up to 16 mg per day) after a two week run-in phase where all RAS-blockers are eliminated. The investigators will then employ a novel mass spectrometry-based quantification method (after run-in and 10 weeks) to capture the concentrations of ten different angiotensin peptides (including angiotensin I and II, angiotensin 1-7 and angiotensin 1-5).

The investigators hypothesize that significant differences exist between angiotensin levels in CKD patients with DRI compared to angiotensin receptor blockers. Specifically, the investigators expect to determine the regulation of the alternative RAS represented by angiotensin 1-7 with proximal versus distal blockade of the system.

Our data might contribute to a more profound understanding of results from registries and clinical trials beyond the clinical effects of RAS blockade. Further, the study's results might help to individualize and optimize RAS-blocking therapy strategies in CKD patients.

Study Overview

• Status: Completed
• Conditions: Hypertension; Proteinuria; Chronic Kidney Disease
• Intervention / Treatment: Drug: Candesartan; Drug: Aliskiren; Other: RAS blockade discontinuation

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna, Department of Internal Medicine III, Division of Nephrology and Dialysis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Chronic kidney disease stages III-IV (defined by modification of diet in renal disease (MDRD) formula)
• Urinary albumin to creatinine ratio (UACR) >300mg/g, UACR >200mg/g if already receiving RAS blockade
• Arterial hypertension

Exclusion Criteria:

• Age <18 years
• Diabetes mellitus type 2 (defined by WHO criteria)
• Chronic kidney disease stage V (end-stage renal disease)
• UACR >3500mg/g
• Severe hypertension (systolic blood pressure >180mmHg)
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SCREENING
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Aliskiren; After a two-week phase where all RAS blockade is eliminated, patients in this arm will commence taking aliskiren 150 mg once daily for 4 weeks. Thereafter, the dose will be increased to 300 mg once daily for another 4 weeks.	Drug: Aliskiren; Other Names: Rasilez; Other: RAS blockade discontinuation; In the initial two weeks of the study, all RAS blockade will be eliminated from the subjects' antihypertensive regimen
ACTIVE_COMPARATOR: Candesartan; After a two-week phase where all RAS blockade is eliminated, patients in this arm will commence taking candesartan 8 mg once daily for 4 weeks. Thereafter, the dose will be increased to 16 mg once daily for another 4 weeks.	Drug: Candesartan; Other Names: Atacand; Other: RAS blockade discontinuation; In the initial two weeks of the study, all RAS blockade will be eliminated from the subjects' antihypertensive regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mass spectrometry RAS peptide quantification	Quantitative RAS peptide changes determined by mass spectrometry after a 2-month treatment with aliskiren or candesartan	2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood pressure	Blood pressure reduction, determined by ambulatory blood pressure measurements at study start and end	2 months
Proteinuria	Proteinuria reduction, measured by urinary albumin/creatinine ratio at study start and end	2 months

Collaborators and Investigators

• Sponsor: Medical University of Vienna

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (ACTUAL): February 1, 2016
• Study Completion (ACTUAL): February 1, 2016

Study Registration Dates

• First Submitted: April 4, 2013
• First Submitted That Met QC Criteria: April 8, 2013
• First Posted (ESTIMATE): April 9, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): March 16, 2016
• Last Update Submitted That Met QC Criteria: March 14, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: renin-angiotensin-system; RAS blockade
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Renal Insufficiency; Urination Disorders; Kidney Diseases; Renal Insufficiency, Chronic; Proteinuria; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Candesartan
• Other Study ID Numbers: EK-Nr. 011/2012